Nodular regenerative hyperplasia (NRH) of the liver is a rare but potentially
devastating disease. There is controversy whether these nodules can lead to
carcinoma. This disease can be associated with portal hypertension leading
to end stage liver disease, requiring a liver transplant.

The authors report 24 cases of diffuse nodular regenerative hyperplasia
of the liver (DNRH) seen in a General Hospital during the last 9 years
(prevalence: 3'1/100,000, incidence: 0'34/100,000).

DNRH was diagnosed in 0.52% of the liver biopsies and 0.72 of the autopsies.
These results suggest that DNHR is probably more frequent than suspected,
and 1 DNRH was seen for each 39 biopsied cases of liver cirrhosis. Fourteen
patients did not have hepatic symptoms. Portal hypertension was present
in 9 cases. The biochemical disturbance most frequently found was a
moderate elevation of GGT and APh, associated with slight elevation
of SGOT, SGPT and bilirubin levels. Normal liver function tests could
be seen (3 cases). Previous exposure to potentially hepatotoxic drugs
or chemicals was discovered in 15 cases (62.5%). Diseases associated
were circulatory disturbances (6 cases), autoimmune disease (5 cases),
hemopathies (5 cases), and visceral carcinomas (4 cases). Two patients
were recipients of renal transplant.

Nodules distributed through the whole liver tissue were found in 16
cases, while 8 patients showed areas of normal parenchyma in their livers.
Impairment of small hepatic vessels was detected in 16 cases. Some uneven
cytologic findings were discovered: clusters of small basophilic cells
(4 cases), large clear cells (8 cases), and dysplastic hepatocytes (10
cases), which suggests that DNRH could be a preneoplastic condition.

Micronodular transformation (nodular regenerative hyperplasia) of
the liver: a report of 64 cases among 2,500 autopsies and a new classification
of benign hepatocellular nodules.

Wanless IR.

Department of Pathology, Toronto Western Hospital, Canada.

Hepatology 1990 May;11(5):787-97 Abstract quote

Nodular regenerative hyperplasia is defined by hepatocellular nodules
distributed throughout the liver in the absence of fibrous septa between
the nodules. Most reports have been single cases so that the prevalence
and clinical significance of nodular regenerative hyperplasia is uncertain.

In this study, the hepatic histology of 2,500 consecutive autopsies
was reviewed. A spectrum of nodular transformation was found with nodular
regenerative hyperplasia present in 2.6% of autopsy livers and qualitatively
similar but lesser degrees of nodular transformation in a further 10.2%.
Nodular transformation was also seen in 47% of livers with cirrhosis
and 69% with incomplete cirrhosis. Obliteration of many small portal
veins was seen in all cases with nodular regenerative hyperplasia, but
only 4.7% of these had evidence of portal hypertension. The prevalence
of various clinical states was compared in nodular regenerative hyperplasia
and in controls. The results confirm, extend and quantify the spectrum
of associated diseases. Nodular regenerative hyperplasia occurs in 5.6%
of individuals over age 80 and with increased frequency in patients
with systemic arteritis, polymyalgia rheumatica, massive tumor infiltration
and mineral oil deposition. Nodular regenerative hyperplasia appears
to be the hepatic analogue of arterial and arteriolar nephrosclerosis.

A new classification of nodular transformation is proposed that encompasses
the spectrum of lesions described here and the previously defined entities
of focal nodular hyperplasia, partial nodular transformation and "cirrhosis
telangiectasia hepatis."

The major conclusion is that nodular regenerative hyperplasia is a
secondary and nonspecific tissue adaptation to heterogeneous distribution
of blood flow and does not represent a specific entity.

DISEASE ASSOCIATIONS

CHARACTERIZATION

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Nodular regenerative hyperplasia of the liver and antiphospholipid
antibodies: report of two cases and review of the literature.

Nodular regenerative hyperplasia of the liver (NRHL) is a rare disorder
characterized by diffuse micronodular transformation of the hepatic
parenchyma without fibrous septa between the nodules. This condition
appears to be associated in many occasions with systemic autoimmune
diseases.

We describe two new patients with NRHL in whom antiphospholipid antibodies
(aPL) were detected in their sera and review the few similar cases reported
previously. We also discuss the possible relationship between aPL and
NRHL and suggest that these antibodies may play a role in the pathogenesis
of some cases of NRHL, specially those with an associated antiphospholipid
syndrome.

BUDD-CHIARI SYNDROME

Nodular regenerative hyperplasia of the liver in Budd-Chiari syndrome:
CT and MR features.

Rha SE, Lee MG, Lee YS, Kang GH, Ha HK, Kim PN, Auh YH.

Department of Radiology, University of Ulsan Asan Medical Center,
Seoul, South Korea.

Abdom Imaging 2000 May-Jun;25(3):255-8 Abstract quote

We report the imaging findings of spiral computed tomography (CT),
magnetic resonance (MR) imaging, and MR angiography in a patient with
nodular regenerative hyperplasia of the liver associated with Budd-Chiari
syndrome.

OBJECTIVE: In a recent review of hepatocellular carcinoma (HCC) in
North American residents, we were surprised to learn that 42.6% of these
tumors in the 1980-1993 consultation files of the Armed Forces Institute
of Pathology had arisen in noncirrhotic livers. We subsequently noted
that the nonneoplastic livers of a number of these had nodular regenerative
hyperplasia (NRH), a condition that has been associated with liver cell
dysplasia, a putative premalignant lesion. To investigate the possibility
that NRH might be a precursor of HCC, we studied those cases in which
there was an association of HCC and NRH and examined the possible role
of portal vein obstruction in NRH occurring in livers with HCC.

METHODS: Subjects were selected based on study criteria and histological
slides, clinical/autopsy records were reviewed, and features of neoplastic
and nonneoplastic liver were noted. Simple statistical comparisons were
made between the groups with and without NRH with respect to defined
variables.

RESULTS: Of 804 patients suitable for study, 342 were noncirrhotic,
and 23 of these had NRH. Mean age of patients with NRH was 65 +/- 13.6
(SD) yr. Seventeen of these (73.9%) had liver cell dysplasia, and 16
(69.6%) had portal venous invasion. Liver cell dysplasia occurred in
a significantly greater proportion of those with NRH than those without
(p < 0.01), but there was no significant difference between both groups
with regard to portal venous invasion. Three patients (13%) had received
chemotherapy and/or radiotherapy before diagnosis of NRH.

CONCLUSIONS: These findings may be due to the development of HCC within
the dysplastic foci that occur in livers with NRH, but the findings
do not exclude the converse possibility that NRH may also develop in
a noncirrhotic liver with HCC, secondary to portal venous invasion with
portal vein occlusion. The temporal relationship between HCC and NRH
is probably determined in each case by the particular interaction of
multiple pathogenetic factors. Among patients with HCC, factors other
than the portal vein obstruction by tumor invasion may play a role in
the pathogenesis of NRH.

CELIAC DISEASE

Nodular regenerative hyperplasia of the liver in a patient with
celiac disease.

Riestra S, Dominguez F, Rodrigo L.

Digestive Unit, Hospital Valle del Nalon, Asturias, Spain.

J Clin Gastroenterol 2001 Oct;33(4):323-6 Abstract quote

We present the case of dual adult celiac disease and liver disease
with portal hypertension (esophageal varices); a percutaneous liver
biopsy was compatible with nonspecific reactive hepatitis. Clinically,
celiac disease was characterised by poor response to a gluten-free diet,
with the development of a biochemical cholestasis and marked malnutrition.

Our patient died of cerebral hemorrhage, at the age of 50 years, without
associated risk factors. The necropsy demonstrated the existence of
a nodular regenerative hyperplasia of the liver, splenic atrophy, gelatinous
transformation of the bone marrow, and lymphocytic colitis.

We discuss the different types of liver disorders associated with celiac
disease and the possible relation between nodular regenerative hyperplasia
and celiac disease, based on immunologic mechanisms.

First Department of Pathology, Juntendo University, School of Medicine,
Japan.

Liver 2000 Oct;20(5):366-73 Abstract quote

AIMS/BACKGROUND: Among patients with collagen diseases, liver enzyme
abnormalities are a relatively common phenomenon. To establish the liver
pathology in collagen diseases, detailed pathologic studies were performed
on the hepatic diseases in many patients, including various kinds of
collagen diseases.

RESULTS: Liver diseases were divided into three groups: hepatic arteritis,
liver diseases associated with collagen diseases (primary biliary cirrhosis,
PBC; autoimmune hepatitis, AIH; nodular regenerative hyperplasia of
the liver, NRH) and other liver diseases. Hepatic arteritis presenting
the features of the PAN type of necrotizing arteritis was found in 27
autopsy patients. The incidence of arteritis in autopsy patients was
100% in PAN and 8.3-25% in other collagen diseases. Primary biliary
cirrhosis was observed in 9 patients, 7 of whom (3 with SSc, 2 with
RA, 1 with PM and DM, and 1 with MCTD) had antimitochondrial antibodies
(AMA)-positive PBC, and 2 SLE patients had AMA-negative PBC. Three patients
(2 with SLE and 1 with MCTD) were diagnosed clinicopathologically as
having AIH. However, 3 patients (1 with SLE, 1 with MCTD and 1 with
PM and DM) with clinical, biochemical and serologic data indicating
probable AIH were excluded from the group with AIH association because
of the liver histology (no characteristic features of AIH) and clinical
course. These results indicated that data without histologic assessments
of the liver are not adequate for diagnosing AIH in collagen diseases.
Nodular regenerative hyperplasia of the liver was observed in 7 patients
(5 with SLE, 1 with SSc and 1 with PAN).

CONCLUSION: The present study offers data that are useful for the diagnosis
and treatment of patients with collagen diseases and liver abnormalities.

CONGENITAL ABSENCE OF PORTAL VEIN

Congenital absence of portal vein with nodular regenerative hyperplasia
of the liver.

Department of Radiology, University of Brescia, Spedali Civili,
Italy.

Eur Radiol 2000;10(5):820-5 Abstract quote

Congenital absence of the portal vein is a very rare anomaly. The intestinal
and splenic venous drainage bypasses the liver and drain into the inferior
vena cava (IVC).

Two cases of such anomaly are described. Both cases were investigated
by US coupled with echo-colour Doppler examination, CT and MR imaging,
followed by digital subtraction angiography (DSA) and liver biopsy.

In the first case the splenic and superior mesenteric vein formed
a venous trunk which emptied directly into the IVC; in the second case,
the splanchnic blood flowed into a dilated hepatofugal inferior mesenteric
vein which connected to the left internal iliac vein. In both cases
nodular regenerative hyperplasia of the liver was present, presumably
due to an abnormal hepatic cell response to the absent portal flow.

The particular contribution of MR imaging to the diagnosis of both
vascular abnormalities and liver parenchyma derangement and its advantages
over the other diagnostic techniques is emphasized. The clinical and
radiological features of 17 previously reported cases are reviewed.

POLYARTERITIS NODOSA

Nodular regenerative hyperplasia of the liver associated with polyarteritis
nodosa.

Nakanuma Y, Ohta G, Sasaki K.

Arch Pathol Lab Med 1984 Feb;108(2):133-5 Abstract quote

Nodular regenerative hyperplasia (NRH) of the liver was found at autopsy
in a 74-year-old woman with generalized polyarteritis nodosa.

Such an association is very rare. Small hepatic arteries displayed
necrotizing angiitis with thrombotic occlusion of parallel-running portal
veins in the portal tracts. Sinusoidal dilatations with an atrophy and
occasional dropout of the hepatocytes were often found in the extranodular
parenchyma around and between the hyperplastic nodules of hepatocytes.

The arterial, portal venous, and sinusoidal lesions of the liver were
prominent in the present case, and all might be contributing factors
for the development of NRH of the liver.

SCHNITZLER'S SYNDROME

A case of Schnitzler's syndrome with nodular regenerative hyperplasia
of the liver.

Lauwers A, Chouvy V, Mosnier JF, Misery L, Alexandre C.

Rheumatology Department, Bellevue Hospital, Saint-Etienne, France.

Rev Rhum Engl Ed 1999 May;66(5):281-3 Abstract quote

Schnitzler's syndrome is a rare condition of urticaria, macroglobulinemia,
and sclerotic bone lesions.

We report a case in a 70-year-old man in whom inflammatory polyarthralgia
was followed by a nonpruritic urticarial eruption with a moderate decline
in general health. Laboratory tests showed inflammation and a modest
isolated peak of monoclonal IgM kappa. There was no evidence of Waldenstrom
macroglobulinemia. Schnitzler's syndrome was considered. However, an
ultrasound scan of the abdomen done because of mild gamma-glutamyl-transferase
elevation disclosed multiple hepatic lesions. The liver histology showed
incipient nodular regenerative hyperplasia. Only about 30 cases of Schnitzler's
syndrome have been reported since the seminal description in 1972. Hepatic
involvement was a common but nonspecific finding, and we found no cases
with nodular regenerative hyperplasia. However, this abnormality is
often found in patients with autoimmune or hematological disorders.

The pathogenesis of Schnitzler's syndrome remains unknown, but the
possibility of progression to a hematological malignancy requires prolonged
follow-up.

SJOGREN'S SYNDROME

Nodular regenerative hyperplasia of the liver and primary Sjogren's
syndrome.

Nodular regenerative hyperplasia (NRH) of the liver is a rare entity
associated with autoimmune diseases, hematologic disorders and therapy
with immunosuppressive agents.

We describe a patient with primary Sjogren's syndrome and NRH of the
liver, the first report of this association. The pathogenesis of NRH
is not clear, but the presence of some type of circulatory disorder
is suspected.

SYSTEMIC LUPUS ERYTHEMATOSUS

Nodular regenerative hyperplasia of the liver in systemic lupus
erythematosus. The relationship with anticardiolipin antibody and lupus
anticoagulant.

We describe a patient with SLE complicated by NRH, who did not show
neither aCL nor LA activity. This case suggests that the pathogenesis
of NRH in patients with autoimmune diseases is heterogeneous and not
confined to aCL and LA.

SYSTEMIC SCLEROSIS

Nodular regenerative hyperplasia of the liver in a patient with
systemic sclerosis.

Department of Internal Medicine, Keio University School of Medicine,
Japan.

Clin Rheumatol 1996 Nov;15(6):613-6 Abstract quote

We report on a 33-year-old female patient with systemic sclerosis and
nodular regenerative hyperplasia of the liver (NRHL).

A needle biopsy of the patient's liver did not reveal the histology
of NRHL or liver cirrhosis at her first visit to our hospital, when
portal hypertension was demonstrated by percutaneous transhepatic portography.
After 11 years, the patient died of hepatic and renal failure.

At the time of autopsy, multiple nodules were found in the liver, and
a microscopic examination showed a histology compatible with NRHL. It
is suggested that the immunological disturbance was related to the patient's
portal hypertension and NRHL.

PATHOGENESIS

CHARACTERIZATION

INTERLEUKIN 6

Coexpression of IL-6 and soluble IL-6R causes nodular regenerative
hyperplasia and adenomas of the liver.

Studies with tumor necrosis factor p55 receptor- and interleukin-6
(IL-6)-deficient mice have shown that IL-6 is required for hepatocyte
proliferation and reconstitution of the liver mass after partial hepatectomy.

The biological activities of IL-6 are potentiated when this cytokine
binds soluble forms of its specific receptor subunit (sIL-6R) and the
resulting complex interacts with the transmembrane signaling chain gp130.

We show here that double transgenic mice expressing high levels of
both human IL-6 and sIL-6R under the control of liver-specific promoters
spontaneously develop nodules of hepatocellular hyperplasia around periportal
spaces and present signs of sustained hepatocyte proliferation. The
resulting picture is identical to that of human nodular regenerative
hyperplasia, a condition frequently associated with immunological and
myeloproliferative disorders. In high expressors, hyperplastic lesions
progress with time into discrete liver adenomas.

These data strongly suggest that the IL-6/sIL-6R complex is both a
primary stimulus to hepatocyte proliferation and a pathogenic factor
of hepatocellular transformation.

PORTAL VEIN HEMODYNAMICS

Hepatic hemodynamics in a patient with nodular regenerative hyperplasia.

First Department of Surgery, Kagoshima University School of Medicine,
Japan.

Am J Gastroenterol 1996 May;91(5):1012-5 Abstract quote

Nodular regenerative hyperplasia of the liver is an uncommon condition.
Approximately 50% of these patients develop portal hypertension. Few
previous reports document the site of increased resistance to blood
flow within the liver in this disorder.

We measured Doppler waveform patterns of the right hepatic vein by
pulsed Doppler ultrasonography and portal, wedged hepatic, and free
hepatic venous pressure by intravenous catheter before and after splenectomy
in a 47-yr-old woman with nodular regenerative hyperplasia who presented
with portal hypertension and pancytopenia. Nodular regenerative hyperplasia
was histologically confirmed. Pre- and postoperative measures indicated
a marked difference between wedged hepatic venous pressure and free
hepatic venous pressure, whereas there was little difference between
portal venous pressure and wedged hepatic venous pressure. Doppler waveform
patterns of the right hepatic vein showed an unclear pulsatile flow
pattern with a decreasing reversed phase.

The above data suggest that portal hypertension in nodular regenerative
hyperplasia is primarily sinusoidal, similar to that seen with cirrhosis.

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION

RADIOLOGIC

MR imaging of hepatic nodular regenerative hyperplasia.

Siegelman ES, Outwater EK, Furth EE, Rubin R.

Department of Radiology, Hospital of the University of Pennsylvania,
Philadelphia 19104, USA.

J Magn Reson Imaging 1995 Nov-Dec;5(6):730-2 Abstract quote

Nodular regenerative hyperplasia (NRH), a rare condition that is commonly
associated with noncirrhotic portal hypertension, is not well described
in the MR literature.

Three patients at two institutions were identified who had both abdominal
MR imaging and pathologic evidence of NRH. All examinations were performed
at 1.5 T and included axial T1- and T2-weighted spin-echo (SE) images.
The MR studies were reviewed by two radiologists in consensus. Two patients
had multiple liver lesions that had high signal components on T1-weighted
images and were predominantly isointense with liver on the T2-weighted
images.

One patient had no focal lesions identified. NRH, when visualized on
MR images, appears as multifocal masses with shortened T1 and T2 similar
to liver. NRH should be considered in the differential diagnosis of
hepatocellular tumors, especially in patients with a predisposing condition.

Pseudotumoral presentation of nodular regenerative hyperplasia of
the liver: imaging in five patients including MR imaging.

Nodular regenerative hyperplasia (NRH) of the liver is a condition
characterized by multiple monoacinar regenerative nodules in the absence
of fibrous septa. When these nodules become confluent they may be seen
with sonography or CT. The appearance of these pseudotumoral pattern
of NRH has been scarcely described with MRI.

We present the imaging findings of five patients with NRH and a pseudotumoral
form at sonography. Sonography depicted hyperechoic lesions in four
patients and hypoechoic lesions in another. Computed tomography showed
hypodense lesions with little contrast enhancement in two patients.
Three patients showed subtle focal liver lesions on MRI: isointense
in one, mildly hypointense in another, and minimally hyperintense in
a patient with siderosis.

The dynamic behavior at MRI was similar to the normal liver parenchyma.
Hyperechoic lesions on sonography or hypodense lesions on CT, barely
or not seen on MRI, can be indicative of NRH in an appropriate clinical
setting.

Imaging features of nodular regenerative hyperplasia of the liver
mimicking hepatic metastases.

We described the sonographic, computed tomographic (CT), and magnetic
resonance (MR) imaging features of one atypical case of nodular regenerative
hyperplasia of the liver. The presence of multiple hepatic nodules suggested
the diagnosis of metastatic disease to the liver because of a peripheral
rim of enhancement on CT obtained after intravenous administration of
contrast material and a halo sign on T2-weighted spin-echo MR imaging.
Examination of the pathologic specimen obtained after surgical biopsy
showed that the nodules were made of hepatocytes, with a nodular arrangement
surrounded by peliosis, without fibrosis or cirrhosis.

These findings suggested that peliosis may cause peripheral rim of
enhancement on CT and halo sign on MR imaging. In light of this case,
nodular regenerative hyperplasia of the liver should be considered in
the differential diagnosis of hepatic metastases.

BACKGROUND/AIMS: Nodular regenerative hyperplasia of the liver, is
a noncirrhotic liver disease, characterized by nodules in the hepatic
parenchyma, which clinically presents primarily with manifestations
of portal hypertension. The aims of this study are i) to review the
clinical, histological and diagnostic aspects of 14 documented cases
of NRHL, and ii) to assess the evolution and management of this condition
in the cases reviewed.

METHODOLOGY: The diagnosis of nodular regenerative hyperplasia of the
liver was based on liver biopsy in all cases. Imaging studies (ultrasonography,
computed tomography scan and magnetic resonance imaging scan) were performed
as part of the diagnostic evaluation. Clinical manifestations and biochemical
tests were recorded at the time of diagnosis. Management and prognosis
were also reviewed.

RESULTS: The most common clinical manifestations were those of portal
hypertension, namely splenomegaly, esophageal varices and variceal bleeding.
The histological findings were nodules in the hepatic parenchyma, the
typical histologic feature of nodular regenerative hyperplasia of the
liver, with mild periportal fibrosis and intraportal lymphocytic infiltration.
Biochemical tests showed normal synthetic liver function, as evidenced
by normal serum albumin, bilirubin and prothrombin time. Elevation of
gamma-glutamyl transpeptidase and alkaline phosphatase due to cholestasis
was noted. Management was directed to portal hypertension and variceal
bleeding, with beta-blockers, sclerotherapy, mesenteric-caval shunt
and transjugular intrahepatic portosystemic shunt with satisfactory
results.

CONCLUSIONS: Nodular regenerative hyperplasia of the liver is an uncommon
condition but it should be considered in patients with unexplained portal
hypertension and distinguished from liver cirrhosis, in view of the
differences in the natural history and prognosis. Liver biopsy confirms
the diagnosis. Management is directed primarily to portal hypertension
and variceal bleeding, which is the main source of mortality. Liver
failure is uncommon due to satisfactory preservation of liver function.

VARIANTS

FAMILIAL

Familial occurrence of nodular regenerative hyperplasia of the liver:
a report on three families.

BACKGROUND/AIMS: Nodular regenerative hyperplasia of the liver is a
histological lesion usually associated with systemic diseases, haematological
malignancies, or drugs. Its prognosis depends on portal hypertension,
which usually is well tolerated and requires medical management only.

PATIENTS: Three unrelated families, in which two sibling adult male
patients presented with nodular regenerative hyperplasia of the liver,
were studied.

METHODS: Complete clinical charts and liver biopsy specimens were available
for all patients. In addition, explanted livers were available for examination
for the two transplanted patients.

RESULTS: There was no evidence of any of the various clinical situations
known to be associated with nodular regenerative hyperplasia of the
liver. Portal hypertension was severe, requiring surgical treatment
in two cases. Renal lesions were present in three patients. In two patients,
progressive evolution to liver atrophy and hepatic failure, associated
with renal failure, led to combined liver and renal transplantation.

CONCLUSIONS: This report describes the existence of familial cases
of nodular regenerative hyperplasia of the liver, occurring without
underlying or associated systemic disease, characterised by a poor clinical
course and often associated with progressive renal failure.

Sixteen cases of nodular regenerative hyperplasia of the liver in children
are presented. The patients, 10 girls and 6 boys, were between the ages
of 7 months and 13 years, with a median of 6 years. Clinically, nine
children presented with hepatomegaly or splenomegaly, with and without
signs of portal hypertension. A history of anticonvulsant drug therapy
was obtained in four patients. Associated conditions in the remaining
three cases were Donohue's syndrome, disseminated intravascular coagulation,
and angiomyolipoma of the kidney.

In five patients a clinical diagnosis of primary intra-abdominal tumor
was made. Follow-up showed that six patients died of causes unrelated
to the nodular hyperplasia. Two patients were asymptomatic when last
seen 5 and 18 years after the initial diagnosis of nodular hyperplasia.
Both patients underwent shunt surgery.

No follow-up was available for eight patients. The importance of recognizing
this entity in the pediatric age group, as well as its histopathologic
differential diagnosis, is stressed.

Nodular regenerative hyperplasia of the liver: case report of a
13-year-old girl and review of the literature.

BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is
a multi-acinar regenerative nodular lesion in a non-cirrhotic liver.
It is a rare entity, especially in children, and remains of unknown
aetiology.

OBJECTIVE: NRH is often seen in association with other diseases or
drug intake. In half of patients it is complicated by portal hypertension.
Radiologically, its nodular appearance may look like neoplasia.

RESULTS: We report a case of NRH with enormous hepatomegaly and multiple
huge nodules.

CONCLUSION: We wish to emphasise the importance of open wedge biopsy
to establish diagnosis, since the prognosis of NRH in the absence of
portal hypertension is good. Complications such as rupture of a nodule
are rare.

HISTOLOGICAL TYPES

CHARACTERIZATION

GENERAL

Nodular regenerative hyperplasia of the liver. Report of three cases
and review of the literature.

Viewed microscopically, the nodules consist of regenerative parenchyma
without fibrosis, which are usually smaller than the hepatic lobule.

Nodular regenerative hyperplasia is distinct from other nodular lesions
of the liver such as cirrhosis, partial nodular transformation, focal
nodular hyperplasia, and adenoma. Although nodular regenerative hyperplasia
is seldom reported, it may occur more frequently than it is recognized.

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER

CHARACTERIZATION

SPECIAL STAINS

ALPHA-1 ANTITRYPSIN

Use of alpha-1-antitrypsin staining in the diagnosis of nodular
regenerative hyperplasia of the liver.

Nakhleh RE, Snover DC.

Department of Laboratory Medicine and Pathology, University of Minnesota
Medical School, Minneapolis.

Hum Pathol 1988 Sep;19(9):1048-52 Abstract quote

Nodular regenerative hyperplasia (NRH) is a disorder characterized
by regenerative nodules scattered diffusely throughout the liver without
associated fibrosis. It is most often recognized at autopsy when the
entire liver is available for inspection. The diagnosis of NRH by needle
biopsy is much more subtle.

Since alpha-1-antitrypsin (AAT) expression by hepatocytes in a variety
of liver diseases has suggested that it may represent a marker for regenerative
or damaged hepatocytes, we elected to study the expression of AAT by
immunohistochemical staining of paraffin-embedded tissue of biopsy material
as a possible marker of this diagnosis. Seventeen biopsies of the liver
showing histologic features consistent with NRH were selected and compared
with 20 biopsies of the liver without features of NRH. Eight of the
NRH cases showed periportal granular AAT staining as opposed to only
one of the non-NRH biopsies (P less than .01; Fisher exact test).

These results indicate that AAT expression is increased in the regenerating
compartment (as opposed to the presumably damaged atrophic portion)
of the liver in NRH and suggest that AAT staining may be useful in confirming
the biopsy diagnosis of NRH.

The prolonged half-life of mutant p53 makes feasible its immunocytochemical
detection. In order to assess the pathogenetic role of mutant p53 in
regenerative and neoplastic liver disease we studied its immunohistochemical
expression in cases of hepatic cirrhosis, hepatocellular carcinoma (HCC),
cirrhosis with areas of HCC, hepatocellular adenoma and focal nodular
hyperplasia.

The study included needle and wedge biopsies of 50 cirrhotic livers,
59 HCCs (36 of them with associated cirrhosis), six adenomas and two
focal nodular hyperplasias. Sixty-five HCC fine-needle cytology specimens
were also included in the study. There was no immunohistochemical evidence
of mutant p53 expression in any of the cases of cirrhotic liver (except
for one instance associated with HCC) adenoma or focal nodular hyperplasia.
In contrast p53 was detected in 8.5% of HCC cases in the biopsy series
and 24% of HCC cases in the fine needle aspiration series. In addition,
mutant p53 expression in HCC was positively correlated with tumour grade.
According to grade, the distribution of p53 positive immunoreactivity
among HCCs was as follows: Grade I-II, 0% of cases in the biopsy series
and 9% in the fine needle aspirates; Grade III, 18% in the biopsy series
and 55% in the fine needle aspirates; and Grade IV, 40% in the biopsy
series.

Therefore, mutant p53 expression does not seem to be associated with
benign liver lesions but seems to correlate with the progression of
HCC through various grades of increasing malignancy.

Liver transplantation has been performed in individuals with a pretransplant
clinical diagnosis of cirrhosis but with nodular regenerative hyperplasia
histologically. The purpose of this report is to investigate the results
of liver transplantation in patients proven to have nodular regenerative
hyperplasia post-transplant.

A retrospective review was undertaken of four patients who underwent
liver transplantation with a histologic diagnosis of nodular regenerative
hyperplasia. All were felt to be cirrhotic on clinical grounds. Final
histology of the explanted liver was confirmed by a single pathologist.
Their ages ranged from 39 to 54 years, and three of the four were male.
Three had pretransplant needle liver biopsies, two percutaneous and
one transjugular. All revealed nonspecific reactive changes.

Ultrasound and MRI were interpreted as consistent with cirrhosis in
four of four and three of four cases, respectively. Portal vein flow
was hepatopedal in three and absent in one. Pretransplant clinical characteristics
and frequency were as follows: bleeding varices two, clinical ascites
three, encephalopathy three, and impaired hepatic synthetic function
two. All four patients underwent successful liver transplantation. There
were no episodes of acute rejection. All are alive and well with normal
graft function 2 to 4 years post-transplant.

We conclude the following. 1) Patients with clinical end-stage liver
disease due to underlying nodular regenerative hyperplasia can successfully
undergo transplantation. 2) Nodular regenerative hyperplasia can present
with signs and symptoms of liver failure, is difficult to diagnose by
needle biopsy, and can be difficult to discriminate clinically from
cirrhosis. 3) Although each case must be individually evaluated transplantation
may be the optimal therapy in patients presenting with complications
of liver failure.